Several of the advisory groups with whom we work closely encouraged us to develop radioligands for glutamatergic targets. Here, we describe our ongoing work in animals and in healthy subjects for two such targets: metabotropic glutamate receptor 1 (mGluR1) and transmembrane AMPA receptor regulatory protein &#947;-8 (TARP&#947;-8). Examples of progress made during the prior year are summarized below. 1) We have developed the only radioligand18FFIMXto successfully image the mGluR1 receptor in human brain (Xu et al, J Med Chem 56: 9146-9155, 2013). This work was performed under clinical protocol #13-M-0016, with corresponding NCT number not yet assigned. mGluR1 has been linked to the pathophysiology of several neurological and psychiatric disorders, including Parkinsons disease, Huntingtons disease, stroke, epilepsy, anxiety and stress disorders, drug and alcohol addiction, and pain. In vivo quantification with an appropriate radioligand would help clarify the role of mGluR1 in these diseases, ultimately leading to the development of new therapies. We developed 18FFIMX as a very promising radioligand for mGluR1. This compound has attractive properties for in vivo imaging, including high affinity and selectivity. Our initial investigation in two rhesus monkeys found that 18FFIMX provided excellent imaging of mGluR1s in monkey brain, showing high uptake, appropriate regional distribution (i.e., especially high in cerebellum), fast washout, and high receptor-specific signal. Indeed, it appeared that more than 90% of the initial uptake in the cerebellum was due to specific binding. No uptake was seen in the bones, which suggests that no significant defluorination of the radioligand took place (Xu et al, J Med Chem 56: 9146-9155, 2013). Expanding this work, we are using 18FFIMX in a first-in-human PET imaging study. In eight subjects studied to date, 18FFIMX had high brain uptake, an early time of peak uptake followed by fast washout, and a regional distribution appropriate for mGluR1. The radioligand had a high ratio of specific to nonspecific binding as shown by the range of VT values, from 9.9 mL/cm3 in cerebellum to 1.4 in caudate. Uptake of radioactivity in skull, potentially 18F fluoride ion, was absent. Thus, as in monkeys, 18FFIMX showed promising characteristics for quantifying mGluR1s in humans. 2) In collaboration with Eli Lilly, we are developing a PET radioligand for TARP&#947;-8, which helps mobilize AMPA receptors to the synaptic membrane and is preferentially localized in hippocampus. This work was performed under clinical protocol #14-M-0068, with corresponding NCT#02108015. TARP&#947;-8 is target for which a therapeutic candidate will likely be given to humans within a year, but whose importance as a putative marker of pathophysiology is unknown. In collaboration with Eli Lilly, we are developing a PET radioligand for TARP&#947;-8. An advantage of targeting this or any other TARP is that an antagonist at this protein acts as an indirect AMPA antagonist only at those receptors linked to the particular TARP. A successful radioligand could be used to measure baseline density of TARP&#947;-8 in targeted disorders (epilepsy, schizophrenia), as well as to select an initial dose of the therapeutic candidate. Our initial attempt to develop a PET radioligand failed both in monkeys and in healthy human subjects because the specific receptor bound signal was too low relative to nonspecific binding. We are now actively exploring other analogs that may have greater specific signal (e.g., higher affinity) and less nonspecific binding (e.g., lower lipophilicity). If we develop a successful radioligand, we will perform receptor occupancy studies with Lillys therapeutic candidate. Towards this goal, Drs. Innis and Zarate (Chief, Experimental Therapeutics and Pathophysiology Branch, NIMH) have established a Phase I unit specifically for this target and candidate but whose use can be extended to many others. We are also in the early stages of planning to image TARP&#947;-8 in conjunction with a proof-of-concept study for this therapeutic candidate in epilepsy. TARP&#947;-8 is highly localized in hippocampus. Seizures, which often begin in hippocampus, are induced in part by excessive AMPA receptor activation. Because a TARP&#947;-8 antagonist effectively acts as an indirect AMPA antagonist, such a drug would be expected to have anti-epileptic properties, as has been demonstrated in rats. Furthermore, if we develop a useful radioligand for TARP&#947;-8, it may also be used to explore the pathophysiology of psychiatric disorders e.g., the density of TARP&#947;-8 in schizophrenia.